North of Tyne, Gateshead and North

Cumbria Area Prescribing Committee

Vitamin B12 management guideline

Approved: January 2020

Review: January 2023

Scope of guidance

Vitamin B12 deficiency is a common finding that can affect people of any age but its prevalence

increases among older people. It is reported to affect around 5% of people aged 65 to 74, and 10%

of people aged over 75.1 However, most of these people have no attributable symptoms and do not

have either macrocytosis or anaemia. The routine use of longterm intramuscular hydroxycobalamin

replacement in this setting has led to a high burden of treatment for patients and primary care. This

guideline aims to support clinicians in the interpretation of the results of B12 testing and

management of patients with abnormal results.

Clinical features

The presenting features of B12 deficiency are anaemia, typically macrocytic (e.g. fatigue, lethargy

and dyspnoea) or neurological symptoms (e.g. paraesthesia, numbness, cognitive changes or visual

disturbance (yellow-blue blindness)).

Paraesthesia, typically ‘pins and needles’ of hands and/or feet, are reported by 70% of people with

neurological symptoms.2 The commonest findings on examination are loss of vibration and joint

position sense. Other findings on examination may include pallor, lemon tinge to the skin, glossitis

and oral ulceration. Neuropsychiatric features are reported to include irritability, depression,

psychosis and dementia.

Causes

Vitamin B12 is mainly absorbed in terminal ileum, and this process is aided by intrinsic factor (IF)

produced by gastric parietal cells. However, an additional 1% of dietary cobalamin is believed to be

absorbed along the length of the gastrointestinal tract independent to IF. The human body stores 2-

4mg of B12 (mainly in the liver), which is enough to last for 2-4 years if intake ceases.

Causes of B12 deficiency are gastric atrophy (due to ageing, chronic H. pylori infection or

autoimmune-mediated), bowel resection surgery (e.g. bariatric), Crohn’s disease, malabsorption

(e.g. pancreatic insufficiency or bacterial overgrowth), H. pylori, drugs effecting absorption (e.g.

metformin, H2-receptor antagonists and proton pump inhibitors) and a strict vegan diet without

appropriate supplementation. Pregnancy and oestrogen supplementation may cause reductions in

plasma haptocorrin B12 leading to reductions in measured B12 levels without true deficiency.

Pernicious anaemia

Pernicious anaemia (PA) is the term for autoimmune-mediated gastric atrophy with destruction of

the gastric parietal cells that produce intrinsic factor. It is more likely to occur in people with other

autoimmune disorders (e.g. type 1 diabetes, thyroid disease, Addison’s disease, vitiligo or

hypoparathyroidism). It is reported to have a peak age of onset around 60 years and a prevalence

around 1/1000 in the UK.3,4 PA is the cause of only a small proportion B12 deficiency.

Identification of B12 deficiency

Serum vitamin B12 levels can be measures to test for B12 deficiency. Testing for folate deficiency is

done concurrently as the biochemical pathways and many features of deficiency are closely

interlinked. Interpretation of vitamin B12 levels is complicated by the frequency of asymptomatic

low levels of uncertain significance and by the fact that patients with strong clinical features of B12

deficiency who respond to replacement therapy may have vitamin B12 levels within the reference

range.

Elevated levels of methylmalonic acid (MMA) and total plasma homocysteine (tHcy) are alternative

biomarkers of B12 deficiency. However, both can also be elevated in older age and in the presence

of renal impairment.7 Intrinsic factor antibodies (IFAB) and gastric parietal cell antibodies (GPCAB)

have been found in the serum of some people with PA but it is unknown if they have any pathogenic

role. IFAB have a high specificity (98 to 99%) but a low sensitivity (around 50%) for the detection of

PA. False positive IFAB are associated with other autoimmune diseases and older age.5,6

Routine use of these tests in unselected patients is not recommended but may be useful in specific

situations. IFAb should be measured where there is a strong clinical suspicion of B12 deficiency

despite a B12 level within the normal range or in situations such as pregnancy where the normal

range is uncertain. MMA and tHcy testing cannot be sent from primary care and if it is felt that they

are required testing should be discussed with haematology. Please note that IFAb testing, MMA and

tHcy all need to be tested before B12 replacement is commenced.

Pregnancy and oestrogen containing contraceptives

Falls in serum vitamin B12 levels are a normal part of pregnancy and thought to be physiological. In

the absence of symptoms of deficiency low levels are uninterpretable. If symptomatic check IFAb as

these may be useful in establishing the aetiology in this group. If IFAbs are positive treat as

pernicious anaemia. If IFAb are negative but there is a strong clinical suspicion of B12 deficiency

then give 3 doses of im hydroxycobalamin to cover preganancy and reassess 2 months post-partum.

For non-specific asymptomatic low B12 levels repeating B12 testing 2-3 months post-partum is

adequate.

The interpretation of B12 results in women taking oestrogen containing HRT or oral contraception is

difficult and ideally levels should only be checked when there is clinical suspicion of B12 deficiency.

Asymptomatic mild reductions in B12 levels are difficult to interpret and can usually be managed

with dietary advice of supplementation.

Neuropsychiatric changes

Correction of low B12 levels in the absence of macrocytic anaemia or peripheral neuropathy had no

effect compared to placebo on psychiatric state or well-being in people over age 65.8 No correlation

has been detected between low B12 levels and cognitive decline in longitudinal studies.9 Nor have

intervention studies demonstrated a clear benefit for cognition with B12 supplementation with

borderline deficiency (typically in the range 136 to 200ng/L).10-14 There is also only limited correlation

between low B12 levels (136-203 ng/L) in older people with regards to either the development of

macrocytosis or anaemia.15 In addition, no strong association has been found between borderline

B12 levels and peripheral nerve function.16

References

1. Clarke R, Grimley Evans J, Schneede J, et al. Vitamin B12 and folate deficiency in later life.

Age Ageing 2004; 33: 34-41.

2. Healton EB, Savage DG, Burst JCM, et al. Neurologic aspects of cobalamin deficiency. Medicine

1991; 70: 229-45.

3. Scott E. Prevalence of pernicious anaemia in Great Britain. J Coll Gen Pract 1960; 3: 80-4.

4. Toh B, van Driel IR, Gleeson PA. Pernicious anemia. N Eng J Med 1997; 337: 1441-8.

5. Rose MS, Chanarin I, Doniach D, et al. Intrinsic factor antibodies in absence of pernicious anaemia:

3-7 year follow-up. Lancet 1970; 2: 9-12.

6. Bunting RW, Bitzer AM, Kenney RM, et al. Prevalence of intrinsic factor antibodies and vitamin

B12 malabsorption in older patients admitted to a rehabilitation hospital. J Am Geriatr Soc 1990; 38:

743-7.

7. Morris MS, Jacques PF, Rosenberg IH, et al. Elevated serum methylmalonic acid concentrations are

common among elderly Americans. J Nutr 2002; 132: 2799-803.

8. Hughes D, Elwood PC, Shinton NK, et al. Clinical trial of the effect of vitamin B12 in elderly subjects

with low serum B12 levels. BMJ 1970; 2: 458-60.

9. Rosenberg IH. Effects of folate and vitamin B12 on cognitive function in adults and the elderly.

Food Nutrition Bulletin 2008; 29: 2: S132-42.

10. Eastley R, Wilcock GK, Bucks RS. Vitamin B12 deficiency in dementia and cognitive impairment:

the effects of treatment on neuropsychological function. Int J Geriat Psychiatry 2000; 15: 226-33.

11. Hvas A, Juul S, Lauritzen L, et al. No effect of vitamin B-12 treatment on cognitive function and

depression: a randomized placebo controlled study. J Affect Disord 2004; 81: 269-73.

12. Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B-12 with or without folic acid on

cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-

controlled trial. Am J Clin Nutr 2006; 84: 361-70.

13. Moore E, Mander A, Ames D, et al. Cognitive impairment and vitamin B12: a review. Internat

Psychogeriatr 2012; 24: 541-56.

14. Kwok T, Lee J, Ma RC, et al. A randomized placebo controlled trial of vitamin B12

supplementation to prevent cognitive decline in older diabetic people with borderline low serum

vitamin B12. Clin Nutrition 2017; 36: 1509-15.

15. den Elzen WPJ, van der Weele GM, Gussekloo J, et al. Subnormal vitamin B12 concentrations and

anaemia in older people: a systematic review. BMC Geriatrics 2010; 10: 42.

16. Miles LM, Mills K, Clarke R, et al. Is there an association of vitamin B12 status with neurological

function in older people? A systematic review. Br J Nutrition 2015; 114: 503-8